Journal
CANCER RESEARCH
Volume 82, Issue 8, Pages 1617-1632Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-3870
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Funding
- Deutsche Forschungsgemeinschaft [SFB 1039, GRK 2158, GRK 2336]
- Deutsche Krebshilfe [70114051]
- Wilhelm-Sander Foundation [2019.082.01]
- LOEWE Center for Translational Medicine and Pharmacology
- LOEWE Center Frankfurt Cancer Institute (FCI) - Hessen State Ministry for Higher Education, Research and the Arts
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Increased levels of ether-phosphatidylserine (ePS) in tumors are associated with tumor-associated macrophage (TAM) expansion and tumor growth. Inhibiting the production of ePS by targeting phosphatidylserine synthase PTDSS1 reduces tumor growth and TAM infiltration.
An altered lipidome in tumors may affect not only tumor cells themselves but also their microenvironment. In this study, a lipidomics screen reveals increased amounts of phosphatidylser-ine (PS), particularly ether-PS (ePS), in murine mammary tumors compared with normal tissue. PS was produced by phosphatidylserine synthase 1 (PTDSS1), and depletion of Ptdss1 from tumor cells in mice reduced ePS levels accompanied by stunted tumor growth and decreased tumor-associated macrophage (TAM) abundance. Ptdss1-deficient tumor cells exposed less PS during apoptosis, which was recognized by the PS receptor MERTK. Mammary tumors in macrophage-specific Mertk-/- mice showed similarly suppressed growth and reduced TAM infiltration. Transcriptomic profiles of TAMs from Ptdss1-knockdown tumors and Mertk-/- TAMs revealed that macrophage proliferation was reduced when the Ptdss1/Mertk pathway was targeted. Moreover, PTDSS1 expression correlated positively with TAM abundance but negatively with breast carcinoma patient survival. PTDSS1 thus may be a target to modify tumor-promoting inflammation. Significance: This study shows that inhibiting the production of ether-phosphatidylserine by targeting phosphatidylserine syn-thase PTDSS1 limits tumor-associated macrophage expansion and breast tumor growth.
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